Polyhydroxy alkyl mercapto mercurial diuretics



United States Patent Ofilice POLYHYDROXY ALKYL MERCAPTO MERCURIALDIURETICS Lincoln H. Werner and Caesar R. Scholz, Summit, N. J.,assignors to Ciba Pharmaceutical Products, Incorporated, Summit, N. J.,a corporation of New Jersey No Drawing. Application March 28, 1951,Serial No. 218,088

6 Claims. (Cl. 260-270) A primary object of the present invention is theembodient of a new group of mercurial diuretics which are free from theaforementioned defects and disadvantages of known compounds of thistype. This object is realized, briefly stated, by combining the organicmercurial with a polyhydroxythiol of the structure HOCH2(CHOH)nCH2SHwherein n is one of the integers 1, 2, 3, 4 or 5, the resulting productsexhibiting superior therapeutic properties with particular reference tocardiac toxicity, chronic renal toxicity, and tissue necrosis at thesite of injection.

101s corresponding to glycerol, xylitol, sorbitol, mannitol, etc.

A further object of the invention is the realization of maximumdetoxification of the aforementioned organic mercurial diuretics, withparticular reference to those which contain the structure:

wherein R stands for hydrogen or lower alkyl, such as methyl, ethyl,propyl or butyl, and n has the previously indicated significance. Thisobject is realized according to the present invention, briefly stated,by the provision of a --CONH group adjacent the mercurated side chainand also of a -COOH grou in accordance with the following formula:

wherein R and n have the previously indicated significance, -OC-RCO-represents the divalent diacyl radical derived from a dicarboxylic acid,and M stands for hydrogen, an alkali metal such as sodium, potassium,lithium or the like, or an alkaline earth metal such as calcium.

The precise character of the -OC-RCO is of secondary importance, so thatthe R radical aliphatic, alicyclic, carbocyclic or heterocyclic in ter.Thus, for example, the -OC-RCO-- group may be derived from camphoricacid, N-carboxy succinamic acid, phthalic acid, Z-carboxy-phenoxyaceticacid, quinolinic acid and many others.

The new compounds of the present invention are congroup may becharacvol. 76, page 2,705,716 Patented Apr. 5, 1955 veniently producedby reacting a compound having the structure HOOCR-CONH-CH2CHOR CH2HgORor its salts, wherein OCRCO- and R have the previously indicatedsignificance and R is hydrogen or acetyl, with a polyhydroxy thiol, inwater or in a dilute aqueous solution of methanol, acetone or the like.resultant reaction product is then preclpitated from the solvents suchas acetone, methanol, ethanol, dioxane and the like. The precipitatedproduct is filtered off, washed and dried, whereupon it is obtained as ahighly watersoluble powder.

ternatively, the organic mercurial and the polyhydroxy thiol are mixedin appropriate amounts in water solution, which is then frozen and driedfrom the frozen state to yield a product which is stable and readilysoluble upon mere addition of water.

In the following examples, the greater detail with reference examplesare presented solely by way not by way of limitation. In the examples,parts by weight bear the same relation to parts by volume as do grams tomilliliters. Temperatures are expressed in degrees centigrade.

Example 1 17.6 parts by weight of2-[N-(2-hydroxy-3-hydroxymercuripropyl)-carbamyl]-nicotinic acid,prepared according to Hartmann and Panizzon, U. S. Patent No. 2,136,503,are dissolved in 20 parts by volume of 2- normal sodium hydroxidesolution. An equimolecular amount of l-thiosorbitol dissolved inZO-parts by volume of water is added and the solution filtered. 400parts by volume of acetone are added to the filtrate and the resultantprecipitate is washed with fresh acetone and then dried in vacuo. Theresultant product, the 2-[N-2-hydroxy3-{D-gluco-pentahydroxyhexyl-mercaptomercuri}-propyl)-carbamylJ-nicotinic acid sodium salt is very soluble in water;it melts at 79 (with decomposition) and corresponds to the formula COONaCONHOH2?HCHrHg-SGH1 OH H OH HOAH H OH H6011 HzOH Example 2 4.41 parts byweight of 2-[N-(2-hydroxy-3-hydroxymercuripropyl)-carbamyl]-nicotinicacid are dissolved in parts by volume of l-normal sodium hydroxidesolution and then an equimolecular quantity of aqueous thioglycerol isadded. After filtering the solution, the reaction product isprecipitated from the filtrate by adding 100 parts by volume of acetone.The precipitate is separated by filtration, washed with fresh acetoneand dried in vacuo. The obtained product, the 2-[N(2-hydroxy- 3-{2,3dihydroxypropylmercaptomercuri}-propyl) carbamyll-nicotinic acid sodiumsalt, is soluble in water. It melts at 7478 (with decomposition) andcorresponds to the formula 4.41 parts by weight of2-[N-(Z-hydroxy-S-hydroxymercuripropyD-carbamyl]-nicotinic acid aredissolved in 10 parts by volume of l-normal sodium hydroxide solutionand then an equimolecular quantity of l-thio-xylitol, prepared accordingto Farlow et al., JACS, vol. 70, page 1392 (1948) is added and thesolution filtered. The reaction product is precipitated from thefiltrate by adding 100 parts by volume of acetone. The separatedprecipitate is then washed repeatedly with fresh acetone, whereupon itis dried in vacuo. The product, the 2-[N-(2-hydroxy-3- {D xylote'trahydroxypentyl mercaptomercuri} propyl)-carbamyl]-nicotinic acidsodium salt is very soluble in water. It melts at 73 and corresponds tothe formula N CONH-CHaCH-CH:Hg-S-CH: H H E H OH H OH

(JHQOH (D-xylo) Example 4 of 2- [N- (2-hydroxy-3 -hydroxy- 4.41 arts byweight p dissolved in mercuripropyl)-carbamyll -nicotinic acid arel-normal tion. Then an equimolecular quantity of l-thiomannitol,prepared according to Farlow et al. (supra), in 2 parts by volume ofwater is added and the solution filtered. The product is precipitatedfrom the filtrate by adding 100 parts by volume of acetone. Theprecipitate is separated, washed repeatedly with fresh acetone and driedin vacuo. The product, the 2-[N-(2-hydr0xy-3-{D-manno-pentahydroxyhexylmercaptomercuri} propyl) carbamyl] nicotinic acid sodium salt, isreadily soluble in water. It melts at 64 and corresponds to the formulaCOONa C ONE-C HzCHF-OHaHg-S-CH;

H HO E H OH H OH

HsOH (D-manno) Example 5 4.5 parts by weight ofN-[N-(2-methoxy-3-hydroxymercuripropyl)-carbamyl] -succinamic acid,prepared according to Geiger, U. S. Patent No. 2,208,941, are dissolvedin parts by volume of l-normal sodium hydroxide solution, anequimolecular amount of 1-thiosorbitol is added, and the solutionfiltered. The reaction product is precipitated from the filtrate byadding 150 parts by volume of acetone and after being isolated, iswashed repeatedly with fresh acetone, after which it is dried in vacuo.The product, theN-[N-(2-methoxy-3-{D-gluco-pentahydroxyhexylmercaptomercuri}-propyl)-carbamyl]-succinamicacid sodium salt, is readily soluble in water; it melts at 90-95 andcorresponds to the formula 5.3 parts by weight ofN-(2-methoxy-3-acetoxy-mercuripropyl)-camphoramic acid, preparedaccording to U. S. Patent No. 2,117,901, are dissolved in 10 parts byvolume of 2-normal sodium hydroxide solution, an equimolecular quantityof thiosorbitol in 5 parts by volume of water is added and the solutionfiltered. The reaction product is precipitated by adding parts by volumeof acetone to the filtrate, whereupon the precipitate is separated,washed repeatedly with fresh acetone, and dried in vacuo. The product,the N-[2-methoxy-3-(D-gluco-pentahydroxyhexyl-mercaptomercuri)-propyl]-camphoramic acid sodium sodium salt, is somewhat hygroscopic and verysoluble in water; it melts at 100-130 (with decomposition) andcorresponds to the formula H20 CH; mo

ooNrr-crnoH-orrmg-s-om CH: HCOH HO H noon

H OH

Example 7 2.2 parts by mercuripropyl)-carbamyl] -phenoxyacetic acid (B.I. 0 S report 766, page 122) are dissolved in 2.3 parts by volume of2-normal sodium hydroxide solution and then an equimolecular quantity ofl-thiosorbitol in 1 part by volume of water is added. The solution isfiltered and the reaction product precipitated from the filtrate byadding 100 by volume of acetone. The precipitate is isolated, washedrepeatedly with fresh acetone and then dried in vacuo. The product, the1-[N-(2-methoxy-3-{D-gluco-pentahydroxyhexyl mercaptomercuri} propyl)carbamyl] phenoxyacetic acid sodium salt is readily soluble in water; itmelts at 58 (with decomposition) and corresponds to the formula weightof o-[N-(2-methoxy-3-hydroxy- 0 CHzC O 0Na 0 ONH-CH|CH--CH:Hg 8 CH:

CHI H OH HO H H OH

H OH

H1011 (D-gluoo) Example 8 Example 9 9.4 parts by weight of quinolinicacid allyl imide prepared by reacting quinolinic acid anhydride withallylamine, are dissolved in 125 parts by volume of methanol and addedto a solution of 17.5 parts by weight of mer curic acetate dissolved in330 parts by volume of methanol. The mixture is refluxed for 16 hoursand then evaporated to dryness in vacuo. The residue is dissolved in 60parts by volume of l-normal sodium hydroxide solution, treated withactivated carbon and filtered. On standing, the hydroxymercuri-compoundcrystallizes. It is filtered off, washed with water, and dried in vacuo.The product is2-[N-(2-methoxy-3-hydroxymercuripropyl)-carbamyl]-nicotinic acid; it hasa melting point of -190 (with decomposition).

9.1 parts by weight of the last-named mercurated product are dissolvedin 10 parts by volume of 2-normal sodium hydroxide solution. Thesolution is filtered, an equimolecular quantity of l-thiosorbitoldissolved in 10 parts by volume of water, is added to the filtrate, andthe resultant mixture again filtered. The reaction prod- I COONB \NcoNn-omon-cmm-s-om on. n on no r:

n on

H OH

HsOH (D-xlne Example 10 4.41 parts by weight of2-[N-(2-hydroxy-3-hydroxymercuripropyl)-carbamyl].-nicotinic acid aresuspended in parts by volume of l-normal potassium hydroxide solution.On addition of an equimolecular amount of l-thiosorbitol, a clearsolution is obtained, This solution is treated with activated carbon andfiltered. The product is precipitated by diluting the filtrate with 100parts by volume of methanol The separated precipitate is washedrepeatedly with dry methanol until a powdery product is obtained whichis dried in vacuo. The product, the2-[N-(2-hydifoxy-3-{D-gluco-penta-hydroxyhexyl mercaptomercuri} propyl)carbamyl] nicotinic acid potassium salt, melts at 6870. It correspondsto the formula COOK \N GONHCHQ?H*CHIHI SCHI OH H OH HO H H OH

H OH

H2OH (D-gluoo) Example 11 4.41 parts by weight of2-[N-(2-hydroxy-3-hydroxymercuripropyl)-carbamyl]'-nicotinic acid aresuspended in 10 parts by volume of water to which 0.37 part by weight ofcalcium hydroxide is added. The calcium salt forms as a thick gum whichon addition of an equivalent amount of l-thiosorbitol slowly dissolves.The pH is adjusted to 7 by adding a small quantity of calcium hydroxideand the solution filtered. The calcium salt is precipitated by adding100 parts by volume of acetone. After standing the product solidifies,it is broken up and washed repeatedly with dry acetone and then dried invacuo. The product, the 2-.[N-(2-hydroxy-3-{D-glucopentahydroxyhexylmercaptomercuri} propyl) carbamylJ-nicotinic acid calcium salt,decomposes at 150- 160 and has the following formula:

I COOCB/2 4.41 parts by weight of2-[N-(Z-hydroxy-B-hydroxymercuripropyl)-carbamyl]-nicotinic acid aresuspended in 10 parts by volume of water. An equivalent amount ofI-thiosorbitol is dissolved in 10 parts by volume of water and added tothe suspension. A clear solution results which is filtered, frozen anddried in vacuo from the frozen state. The product, the2-[N-(2-hydroxy-3- {D- gluco-pentahydroxyhexyl-mercapt0mercuri}-propyl)- carbamylJ-mcotinic acid, is obtained as a friable mass whichdecomposes between 65 and 90 and has the following formula I OOOH43211011 (D-glueo) Having thus disclosed the invention what is claimedis: 1. An organic mercury compound which corresponds to the formulaMOOC-R-CONHCHzCH-CHzHgS-CH11(CHOH)-CH20H wherein -OCR-CO represents thedivalent diacyl radical derived from a dicarboxylic acid selected fromthe group consisting of camphoric acid, N-carboxy succmamic acid,phthalic acid, Zearboxyphenoxyacetic acid and quinolinic acid, R standsfor a member selected from the group consisting of hydrogen and loweralkyl, M is a member selected from the group consisting of hydrogen,alkali metals and alkaline earth metals, and n is one of the integers 1,2, 3, 4 and 5.

The organic mercurial which corresponds to the formula 1 \N ooNu-omonomn-s-om n H on noon H on 350E H2 0 H a.) 'E

3. The organic mercurial which corresponds to the formula r NaO oC-CHzCHz-C ONH-C ONH-CH2CHCHaHgS-CHa 0 on; HC on HO n neon oH (D-glueo)HaC CH:

Hag

GONHCHzCHCO:Hg-S-CH2 Naooc don; noon so no H n on n on

formula N C ONE-CHrCH-CHaHg-S-CH:

OH: H OH H OH HOE

H1011 (ID- lue) 6. The organic mercurial which corresponds to theformula \N coNn-cmcn-cmm-s-cm OOH: noon m H OH H1103 HaOH -l ReferencesCited in the file of this patent UNITED STATES PATENTS 0 2,557,772Shelton et a1 June 19, 1951 FOREIGN PATENTS 619,515 Great Britain Mar.10, 1949

1. AN ORGANIC MERCURY COMPOUND WHICH CORRESPONDS TO THE FORMULA